Welcome to the Gerland group -
Physics of Complex Biosystems
In physics, interactions between particles follow laws. In biology, interactions between biomolecules serve a function. These very different points of view are beginning to merge as research over the past years has demonstrated how, in some exemplary cases, the laws of physics constrain the implementation of biological function.
We investigate several such cases. For instance, we study how the spatial arrangement and coordination of enzymes determines the efficiency of a multi-step reaction. These spatial arrangements can be natural (as in biomolecular complexes) or engineered with the modern methods of bio-nanotechnology. In both cases, fundamental functional tradeoffs emerge, which must be characterized to understand the optimization of such systems.
Methods from theoretical physics help to describe the functioning of these complex biomolecular systems on a quantitative level, while the biological function leads to new questions, with many parallels in the engineering disciplines. Seen from this perspective, a bacterium is a microscopic bioreactor programmed by evolution to rebuild itself from a variable set of resources and in fluctuating environments. How is this bioreactor programmed? Which strategies enable the control of a diverse set of physico-chemical processes in a way as to robustly produce a highly complex product? Quantitative analysis and modeling facilitates insight into the underlying design principles.
Recent Research Highlights
To quantify gene regulation, a function is required that relates transcription factor binding to DNA (input) to the rate of mRNA synthesis from a target gene (output). Such a 'gene regulation function' (GRF) generally cannot be measured because the experimental titration of inputs and simultaneous readout of outputs is difficult. Here we show that GRFs may instead be inferred from natural changes in cellular gene expression, as exemplified for the cell cycle in the yeast S. cerevisiae. We develop this inference approach based on a time series of mRNA synthesis rates from a synchronized population of cells observed over three cell cycles. We first estimate the functional form of how input transcription factors determine mRNA output and then derive GRFs for target genes in the clb2 gene cluster that are expressed during G2/M phase. Systematic analysis of additional GRFs suggests a network architecture that rationalizes transcriptional cell cycle oscillations. We find that a transcription factor network alone can produce oscillations in mRNA expression, but that additional input from cyclin oscillations is required to arrive at the native behaviour of the cell cycle oscillator.
The efficiency of driving chemical reactions by a physical non-equilibrium is kinetically controlled
An out-of-equilibrium physical environment can drive chemical reactions into thermodynamically unfavorable regimes. Under prebiotic conditions such a coupling between physical and chemical non-equilibria may have enabled the spontaneous emergence of primitive evolutionary processes. Here, we study the coupling efficiency within a theoretical model that is inspired by recent laboratory experiments, but focuses on generic effects arising whenever reactant and product molecules have different transport coefficients in a flow-through system. In our model, the physical non-equilibrium is represented by a drift–diffusion process, which is a valid coarse-grained description for the interplay between thermophoresis and convection, as well as for many other molecular transport processes. As a simple chemical reaction, we consider a reversible dimerization process, which is coupled to the transport process by different drift velocities for monomers and dimers. Within this minimal model, the coupling efficiency between the non-equilibrium transport process and the chemical reaction can be analyzed in all parameter regimes. The analysis shows that the efficiency depends strongly on the Damköhler number, a parameter that measures the relative timescales associated with the transport and reaction kinetics. Our model and results will be useful for a better understanding of the conditions for which non-equilibrium environments can provide a significant driving force for chemical reactions in a prebiotic setting.
Cells have evolved diverse mechanisms that maintain intracellular homeostasis in fluctuating environments. In bacteria, control is often exerted by bifunctional receptors acting as both kinase and phosphatase to regulate gene expression, a design known to provide robustness against noise. Yet how such antagonistic enzymatic activities are balanced as a function of environmental change remains poorly understood. We find that the bifunctional receptor that regulates K+ uptake in Escherichia coli is a dual sensor, which modulates its autokinase and phosphatase activities in response to both extracellular and intracellular K+ concentration. Using mathematical modeling, we show that dual sensing is a superior strategy for ensuring homeostasis when both the supply of and demand for a limiting resource fluctuate. By engineering standards, this molecular control system displays a strikingly high degree of functional integration, providing a reference for the vast numbers of receptors for which the sensing strategy remains elusive.